阅读说明：本技术 一种4-取代5-二氟甲基-3-硝基-1h-吡唑类化合物及其制备方法与应用 (4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound and preparation method and application thereof ) 是由 韩文勇 汪建树 黄开顺 潘丽 赵玉珏 陈永正 于 2019-10-14 设计创作，主要内容包括：本发明属于化学和医药技术领域,提供了4-取代5-二氟甲基-3-硝基-1H-吡唑类化合物及其制备方法与应用；所述化合物具有下式所示结构。本发明的化合物在吡唑结构上引入二氟甲基,提高了吡唑结构的生物活性。由于吡唑骨架具有潜在的生物活性、二氟甲基在药物化学中的重要作用,使该类物质为药物活性分子的制备提供了更多可能。本发明采用两瓶反应体系,使二氟乙胺不与硝基烯烃接触,避免氮杂Michael加成反应的发生,通过非原位制备二氟甲基重氮甲烷与硝基烯烃发生[3+2]环加成反应,成功制得4-取代5-二氟甲基-3-硝基-1H-吡唑类化合物。另外,本发明的制备方法具有反应条件温和、原料易得、底物普适性好的优点。<Image he="183" wi="262" file="DDA0002232202180000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of chemistry and medicine, and provides a 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound, and a preparation method and application thereof; the compound has a structure shown in the following formula. The compound of the invention introduces difluoromethyl on a pyrazole structure, and improves the biological activity of the pyrazole structure. Because the pyrazole skeleton has potential biological activity and the difluoromethyl plays an important role in medicinal chemistry, the substances provide more possibility for preparing medicinal active molecules. The invention adopts a two-bottle reaction system, ensures that difluoroethylamine does not contact nitroolefin, avoids the generation of aza Michael addition reaction, and prepares difluoromethyl diazo by ex-situAlkane and nitroolefin generating [3+2]]And (3) performing cycloaddition reaction to successfully prepare the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound. In addition, the preparation method has the advantages of mild reaction conditions, easily obtained raw materials and good substrate universality.)

1. A4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound having the structure of formula I:

wherein R is H, C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, phenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-cyanophenyl, p-nitrophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethylphenyl, 3, 5-di-methoxyphenylBromophenyl, 1-naphthyl, 2-furyl or 2-thienyl.

2. A process for the preparation of a compound according to claim 1, comprising the steps of:

adopting two bottles of reaction devices, mixing difluoroethylamine, tert-butyl nitrite, acetic acid and an organic solvent in a first reaction bottle, and carrying out diazotization reaction to obtain difluoromethyl diazomethane;

mixing an organic solvent, an acid, an oxidant and nitroolefin in a second reaction bottle, wherein the first reaction bottle is communicated with the second reaction bottle through a conduit, so that difluoromethyl diazomethane gas generated in the first reaction bottle is introduced into the second reaction bottle, and the difluoromethyl diazomethane gas and nitroolefin are subjected to [3+2] cyclization/dehydroaromatization reaction to obtain the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound.

3. The method according to claim 2, wherein the organic solvent is 1, 4-dioxane, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, acetonitrile, benzene, toluene, trifluorotoluene, o-xylene, m-xylene, p-xylene, or mesitylene.

4. The method according to claim 2, wherein the molar ratio of difluoroethylamine, tert-butyl nitrite and acetic acid is 1.5: 1.8-2.0: 0.15-0.2.

5. The preparation method according to claim 2, 3 or 4, wherein the diazotization reaction is carried out at a temperature of 50-110 ℃ for 2-48 h.

6. The method according to claim 2, wherein the acid is formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzoic acid, or p-toluenesulfonic acid.

7. The method according to claim 2, wherein the oxidizing agent is oxygen, ferric chloride, cupric oxide, silver oxide, benzoquinone, or 2, 3-dichloro-5, 6-dicyan-p-benzoquinone.

8. The method according to claim 2, wherein the nitroolefin, the acid and the oxidant are used in a ratio of 0.5: 0.1 to 0.2: 0.5 to 1.0.

9. The method according to claim 2 or 8, wherein the [3+2] cyclization/dehydroaromatization reaction is carried out at a temperature of 50 to 80 ℃ for 2 to 48 hours.

10. Use of a compound according to claim 1 for the preparation of a pharmaceutically active molecule.

Technical Field

The invention relates to the technical field of chemistry and medicine, in particular to a 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound and a preparation method and application thereof.

Background

Pyrazole building blocks are widely present in many important natural products and pharmaceutically active molecules in the fields of organic synthesis and medicinal chemistry. Meanwhile, researches in recent years show that the introduction of difluoromethyl group on pyrazole skeleton can obviously improve the bioactivity of the pyrazole skeleton. The main reason is that difluoromethyl contains a weakly acidic C-H bond, is an isostere of hydroxyl, sulfhydryl and hydroxymethyl, and can regulate the biological activity, metabolic stability and lipophilicity of molecules. In view of the potential biological activity of pyrazole backbone and the important role of difluoromethyl in medicinal chemistry, the synthesis of this class of compounds has been reported gradually.

At present, the difluoromethyl-substituted pyrazole compounds reported in the prior art only comprise 3-difluoromethyl-4, 5-disubstituted-1H-pyrazole compounds (the structure is shown in formula II) and difluoromethyl-substituted pyrazoline compounds (the structure is shown in formula III). That is, the difluoromethyl-substituted pyrazole compound has a relatively small number of compounds, and thus, when the difluoromethyl-substituted pyrazole compound is used as an intermediate, the number of pharmaceutically active molecules that can be prepared is relatively small, and the application of the pharmaceutically active molecules is limited. Therefore, the provision of more difluoromethyl-substituted pyrazole compounds useful for the preparation of pharmaceutically active molecules is a major focus in organic synthesis.

In addition, in the report of difluoromethyl-substituted pyrazole compounds in the prior art, the preparation method of difluoromethyl-substituted pyrazole compounds mainly focuses on using difluoromethyl diazomethane and alkyne as raw materials, adopting difluoromethyl diazomethane prepared in situ or a continuous flow method, and preparing 3-difluoromethyl-4, 5-disubstituted-1H-pyrazole compounds through [3+2] cycloaddition reaction, and the specific reaction mechanism is shown in formula IV.

If alkyne is replaced by electron-deficient olefin, difluoromethyl-substituted pyrazoline compounds can only be obtained through [3+2] cycloaddition reaction, and the specific reaction mechanism is shown in formula V.

Obviously, the synthesis of difluoromethyl substituted pyrazole compounds by using olefin as a substrate and difluoromethyl diazomethane as a building block through a [3+2] cycloaddition reaction is not reported yet and is a scientific difficult problem which needs to be solved urgently.

Disclosure of Invention

In view of the above, the present invention aims to provide a 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound, and a preparation method and an application thereof. The 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound provided by the invention widens the variety of difluoromethyl substituted pyrazole compounds, can be used for further preparing related drug active molecules, and has important application value in drug screening and pharmaceutical industry.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound, which has a structure shown in a formula I:

wherein R is H, C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, phenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-cyanophenyl, p-nitrophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dibromophenyl, 1-naphthyl, 2-furyl or 2-thienyl.

The invention also provides a preparation method of the compound in the technical scheme, which comprises the following steps:

adopting two bottles of reaction devices, mixing difluoroethylamine, tert-butyl nitrite, acetic acid and an organic solvent in a first reaction bottle, and carrying out diazotization reaction to obtain difluoromethyl diazomethane;

mixing an organic solvent, an acid, an oxidant and nitroolefin in a second reaction bottle, wherein the first reaction bottle is communicated with the second reaction bottle through a conduit, so that difluoromethyl diazomethane gas generated in the first reaction bottle is introduced into the second reaction bottle, and the difluoromethyl diazomethane gas and nitroolefin are subjected to [3+2] cyclization/dehydroaromatization reaction to obtain the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound.

Preferably, the organic solvent is 1, 4-dioxane, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, acetonitrile, benzene, toluene, trifluorotoluene, o-xylene, m-xylene, p-xylene, or mesitylene.

Preferably, the molar ratio of the difluoroethylamine to the tert-butyl nitrite to the acetic acid is 1.5: 1.8-2: 0.15-0.2.

Preferably, the temperature of the diazotization reaction is 50-110 ℃, and the time is 2-48 h.

Preferably, the acid is formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzoic acid, or p-toluenesulfonic acid.

Preferably, the oxidant is oxygen, ferric chloride, copper oxide, silver oxide, benzoquinone or 2, 3-dichloro-5, 6-dicyan p-benzoquinone.

Preferably, the dosage ratio of the nitroolefin to the acid to the oxidant is 0.5: 0.1-0.2: 0.5-1.0.

Preferably, the temperature of the [3+2] cyclization/dehydroaromatization reaction is 50-80 ℃ and the time is 2-48 h.

The invention also provides application of the compound in the technical scheme in preparation of pharmaceutically active molecules.

The invention provides a 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound, which has a structure shown in a formula I:

wherein R is H, C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, phenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-cyanophenyl, p-nitrophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dibromophenyl, 1-naphthyl, 2-furyl or 2-thienyl. The compound provided by the invention introduces difluoromethyl on a pyrazole structure, so that the biological activity of the pyrazole structure is improved. Because the pyrazole skeleton has potential biological activity and the difluoromethyl plays an important role in medicinal chemistry, the substances provide more possibility for preparing medicinal active molecules.

The invention also provides a preparation method of the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound in the technical scheme, in the prior art, difluoromethyl diazomethane prepared in situ is used as a building block, a one-pot method is adopted to react with nitroolefin, the difluoromethyl-substituted pyrazole compound cannot be synthesized through a [3+2] cycloaddition reaction, and the difluoromethyl-substituted N-nitrosamine compound is obtained through an aza Michael addition/N-nitrosation process. The invention adopts a two-bottle reaction system, ensures that difluoroethylamine does not contact with nitroolefin, avoids aza Michael addition reaction, and solves the scientific problem by a strategy of performing [3+2] cycloaddition reaction on difluoromethyl diazomethane and nitroolefin through ex-situ preparation. In addition, the preparation method provided by the invention has the advantages of mild reaction conditions, easily available raw materials and good substrate universality.

Drawings

FIG. 1 is a schematic diagram of a preparation method according to the present invention;

FIG. 2 shows a single crystal-X-ray diffraction structure of Compound 4a obtained in example 1;

FIG. 3 is a NMR spectrum of Compound 4a obtained in example 1;

FIG. 4 is a nuclear magnetic resonance carbon spectrum of Compound 4a obtained in example 1;

FIG. 5 shows the NMR fluorine spectrum of Compound 4a obtained in example 1.

Detailed Description

The invention provides a 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound, which has a structure shown in a formula I:

wherein R is H, C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, phenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-cyanophenyl, p-nitrophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dibromophenyl, 1-naphthyl, 2-furyl or 2-thienyl.

The invention also provides a preparation method of the compound in the technical scheme, which comprises the following steps:

adopting two bottles of reaction devices, mixing difluoroethylamine, tert-butyl nitrite, acetic acid and an organic solvent in a first reaction bottle, and carrying out diazotization reaction to obtain difluoromethyl diazomethane;

mixing an organic solvent, an acid, an oxidant and nitroolefin in a second reaction bottle, wherein the first reaction bottle is communicated with the second reaction bottle through a conduit, so that difluoromethyl diazomethane gas generated in the first reaction bottle is introduced into the second reaction bottle, and the difluoromethyl diazomethane gas and nitroolefin are subjected to [3+2] cyclization/dehydroaromatization reaction to obtain the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound.

In the invention, in the first reaction bottle, the mol ratio of the difluoroethylamine to the tert-butyl nitrite to the acetic acid is preferably 1.5: 1.8-2.0: 0.15-0.2, and more preferably 1.5: 1.8: 0.15. In the present invention, the organic solvent is preferably 1, 4-dioxane, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, acetonitrile, benzene, toluene, trifluorotoluene, o-xylene, m-xylene, p-xylene, or mesitylene. The amount of the organic solvent used is not particularly limited, as long as difluoroethylamine, tert-butyl nitrite and acetic acid can be sufficiently dissolved and mixed.

In the invention, the temperature of the diazotization reaction is preferably 50-110 ℃; the time is preferably 2-48 h. In the present invention, the temperature of the diazotization reaction is determined by the slight boiling temperature of the organic solvent in the first reaction flask, and since difluoromethyldiazomethane generated by the diazotization reaction in the first reaction flask is introduced into the second reaction flask in a gaseous state to participate in the [3+2] cyclization/dehydroaromatization reaction, it is necessary to control the organic solvent in the first reaction flask to be in a slight boiling state so that difluoromethyldiazomethane is volatilized in a gaseous state.

In the invention, in the second reaction bottle, the dosage ratio of the nitroolefin, the acid and the oxidant is preferably 0.5: 0.1-0.2: 0.5-1.0, and more preferably 0.5: 0.1: 0.5. In the present invention, the acid is preferably formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzoic acid, or p-toluenesulfonic acid. In the present invention, the oxidizing agent is preferably oxygen, ferric chloride, copper oxide, silver oxide, benzoquinone or 2, 3-dichloro-5, 6-dicyan-p-benzoquinone. In the present invention, the kind of the organic solvent in the second reaction flask is preferably consistent with the organic solvent in the first reaction flask, and will not be described herein.

In the invention, the structure of the nitroolefin is shown as formula VI:

in the formula VI, R is H, C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, phenyl, o-methoxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-methoxyphenyl, m-chlorophenyl, m-bromophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-cyanophenyl, p-nitrophenyl, 3, 4-dimethoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dibromophenyl, 1-naphthyl, 2-furyl or 2-thienyl.

In the invention, the temperature of the [3+2] cyclization/dehydroaromatization reaction is preferably 50-80 ℃, and further preferably 70 ℃; the time is preferably 2-48 h.

In the invention, the first reaction bottle and the second reaction bottle are connected through a conduit; and (3) introducing difluoromethyl diazomethane gas generated in the first reaction bottle into the second reaction bottle at any time, and performing [3+2] cyclization/dehydroaromatization reaction with nitroolefin in the second reaction bottle to obtain the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound.

In the invention, the reactions in the first reaction bottle and the second reaction bottle are carried out simultaneously; if difluoromethyl diazomethane is generated in the first reaction bottle, the difluoromethyl diazomethane is introduced into the second reaction bottle through the conduit to carry out the cyclization/dehydroaromatization reaction of [3+2 ]. In the present invention, the reaction time of the whole system is preferably controlled by the amount of the nitroolefin added in the second reaction flask, and the reaction can be terminated when the solution in the second reaction flask is detected to be free from the nitroolefin by thin layer chromatography, indicating that the reaction is complete. In the invention, when the nitroolefin in the second reaction bottle is not completely reacted, but the reaction speed in the first reaction bottle is slowed or stopped, preferably, difluoroethylamine, tert-butyl nitrite, acetic acid and an organic solvent are added into the first reaction bottle again to carry out diazotization; in the first reaction bottle, difluoroethylamine, tert-butyl nitrite, acetic acid and organic solvent are required to be added again for several times for diazotization, and the diazotization reaction is adjusted according to the adding amount of nitroolefin in the second reaction bottle.

After the [3+2] cyclization/dehydroaromatization reaction is finished, the method preferably comprises the step of carrying out post-treatment on the obtained [3+2] cyclization/dehydroaromatization reaction liquid, and the step of treatment preferably comprises the following steps:

cooling the obtained [3+2] cyclization/dehydrogenation aromatization reaction liquid to room temperature, concentrating, and separating and purifying the obtained concentrated liquid by silica gel column chromatography to obtain the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound.

In the invention, the reagent used for the silica gel column chromatography is preferably a mixture of petroleum ether and dichloromethane, and the volume ratio of the petroleum ether to the dichloromethane in the mixture is preferably 6: 1-2: 1.

FIG. 1 is a schematic diagram of a preparation method provided by the present invention, wherein a reaction flask A is a first reaction flask, difluoroethylamine, tert-butyl nitrite, acetic acid and an organic solvent are added to perform a diazotization reaction to obtain difluoromethyl diazomethane; the reaction bottle B is a second reaction bottle, and organic solvent, acid, oxidant and nitroolefin are added to carry out [3+2] cyclization/dehydroaromatization reaction with difluoromethyl diazomethane gas introduced from the reaction bottle A.

The invention also provides application of the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound in the technical scheme in preparation of pharmaceutically active molecules.

In a specific example of the present invention, 5- (4-bromophenyl) -2- (difluoromethyl) -3-phenyl-7- (trifluoromethyl) pyrazolo [1, 5-a ] pyrimidine was synthesized using 4-phenyl-5-difluoromethyl-3-nitro-1H-pyrazole; TCMDC-124506 pharmaceutical analog 1- (5- (difluoromethyl) -4- (4-fluorophenyl) -1-methyl-1H-pyrazole) -3- (4-fluorophenyl) urea was also prepared from 4- (4-fluorophenyl) -5-difluoromethyl-3-nitro-1H-pyrazole via 5- (difluoromethyl) -4- (4-fluorophenyl) -1-methyl-3-nitro-1H-pyrazole.

The 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compound provided by the invention can be used for preparing pharmaceutically active molecules, and has important application value in the drug screening and pharmaceutical industry.

The following examples are provided to illustrate the 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazole compounds of the present invention and their preparation and use, but should not be construed as limiting the scope of the invention.